The efficient functioning of the immune system is a double-edged sword. Its ability to provide a defense against invasion by hostile foreign organisms such as infectious bacteria, viruses, or even malignant cells is relied upon by vertebrate organisms for their health; indeed, their viability depends upon the success of this protection. On the other hand, there are some undesirable side effects to this efficiency, even as it relates to foreign substances encountered by the host. Not all intrusions of foreign tissue are necessarily hostile. Problems encountered in rejections of skin grafts for burn victims has a long history; the more recent proliferation of procedures which involve organ transplants has brought the problem of foreign tissue rejection to the attention of the general public.
Furthermore, it has come to be understood that allergic responses result from operation of the immune system. Allergens apparently trigger responses which culminate in formation of antibodies some, (IgE), capable of binding to mast cells, to elicit the unpleasant symptomology associated with allergies. These sysmptoms may be merely unpleasant, or may be severe, as are those encountered in patients allergic to certain medications, such as penicillin. The advent of pharmaceutical compositions containing peptide molecules large enough to be immunogenic has magnified the importance of this problem. Peptide pharmaceuticals useful in a variety of treatments such as antiviral and anticancer therapies have recently been made much more readily available through recombinant techniques.
It is common knowledge that attempts to prevent unwanted immune responses have not been particularly successful. For example, efforts are made to match transplant recipients with donors so as to minimize the amount of immunogenic response to foreign materials. Only in the case of identical twins can reasonable success be certain. The limitations of such an approach are so apparent as to warrant no further comment. Alternatively, brute force efforts to suppress the immune system in general, such as administration of anti-mitotic agents may prevent rejection at the expense of the recipient's life due to the resulting susceptibility to infection.
An alternate approach applicable only to preventing tissue rejection is passive immunization of recipients with antibodies directed against the histocompatibility antigens (Davies, D. A. L., et al, Transplant Reviews (1979) 30:18-39). Other approaches also applicable only to the transplant rejection problem have employed treatment of the donor tissue. These are based on the assumption that the rejection response is caused by the histocompatibility antigens on the surface of passenger leukocytes carried on the transplant which leukocytes are not an essential part of the desired tissue per se. In vivo culture of the donor transplant tissue has been used to eliminate passenger leukocytes (Surgery (1977) 81:74-79; Science (1980) 209:283-285; Trans Proc (1982) 8:1094-1098). The donor tissue has also been treated directly with suitable antibodies (Faustman, D., et al, Transplantation (1982) 34:302-305). Copending U.S. application Ser. No. 532,609, filed Sept. 15, 1983, assigned to the same assignee, and incorporated herein by reference, discloses the use of immunotoxins formed by conjugating antibodies with a cytotoxic moiety for pretreatment of donor tissue.
Methods to prevent immune responses to soluble antigens have been largely confined to avoidance of exposure. Patients allergic to certain drugs are treated with alternative formulations when available; hay fever sufferers attempt to stay away from the immunogenic pollen. If avoidance is impossible, one must resort to treating the symptoms.
What is desired is a specific immuntolerance with respect to a particular antigen, leaving the general competence of the immune system intact. None of the foregoing approaches achieve such a selective immunosuppression of the subject. Treatments employed to prevent transplant rejection which are directed toward the host per se generally depress the entire system; treatments of the donor tissue alter the nature of the foreign material introduced. In the case of allergic responses to drugs or to environmental antigens, alteration of the foreign material is either undesirable or impractical. In the present invention, the immune system of the host is selectively and specifically suppressed with respect to a particular immunogen without impairing general immunocompetence. The invention achieves this result by virtue of its specificity for a differentiation antigen on the surface of helper T cells, thus preventing those cells from participating in mounting an immune response against a specified, simultaneously introduced, antigen.